The long-term goal of this Program Project and the Hershey Iron Group is to define the molecular and cellular interactions controlling iron regulation and function. The understanding of 1) the mechanisms of intestinal iron egress; 2) intracellular iron compartmentalization; 3) iron-mediated gene regulation; 4) intracellular iron-regulatory protein flux nd 5) the intricate cellular and molecular feedback mechanisms which maintain iron balance are all areas toward which the Program Project team is expected to contribute. Specifically, the individual aims are 1) to determine the structure, processing and expression of the hemochromatosis disease gene within the in vitro and in vivo systems and particularly in the context of iron challenge; 2) to study the regulation of the iron- regulatory proteins (IRPs) by focusing on post-transcriptional modifications and mechanisms of intracellular translocation following cytokine and iron stimulation; and 3) to understand the cytokine-induced molecular mechanisms effecting iron mobilization and flux within a well- defined, iron-loaded primary hepatocyte culture system. This Program Project draws together three research laboratories within the Pennsylvania State University College of Medicine with i) proven track records in the molecular biological and genetic studies of iron metabolism, ii) complementing research interests; iii) established collaborations and well-recognized synergy. The specific proposals, entitled "Biological function of the hemochromatosis disease gene" (Project 1-Chorney); "Post-transcriptional regulation of iron regulatory proteins" (Project 2-Conner) and "Molecular and cellular control transcriptional regulation of iron regulatory proteins" (Project 2-Conner) and "Molecular and cellular control mechanisms in iron-loaded hepatocytes" (Project 3-Isom) engender a natural connectedness which will facilitate the intellectual movement between systems. The Program Project will receive foundation support from a Core encompassing "Metal Analysis and Molecular Genetics" contained within the broader Division of Research Resources (Billingsley) which will further ensure cogent interactions through the sharing of reagents and technologies. It is anticipated that the group will contribute much to the understanding of the physiological processes underlying iron flux and utilization in both health and disease states such as iron overload and anemia, Alzheimer's disease and malignancy.